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首页> 外文期刊>Current drug targets. CNS and neurological disorders >Mitochondria as therapeutic targets of estrogen action in the central nervous system.
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Mitochondria as therapeutic targets of estrogen action in the central nervous system.

机译：线粒体作为中枢神经系统中雌激素作用的治疗靶标。

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Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca(2+) homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased/enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-x(L), which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca(2+) sequestration. These effects are likely to be enhancedby antioxidant effects of estrogen, preventing the initiation of the deleterious "mitochondrial spiral". The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.
机译：神经元的生存能力和对神经退行性疾病的防御可以通过靶向线粒体功能来降低氧化应激，增加线粒体防御机制或促进能量代谢和Ca（2+）稳态来实现。在接触有毒物质之前接触雌激素可以保护神经元免受广泛的退化性伤害。雌激素诱导的前瞻性防御状态是由复杂的机制介导的，从化学到生化再到基因组，但都集中在线粒体功能的调节上。雌激素通过增加/增强氧化磷酸化和降低ATPase活性来保持ATP水平，从而增加线粒体呼吸效率，从而降低了氧化负荷。此外，雌激素会增加抗凋亡蛋白Bcl-2和Bcl-x（L），从而阻止渗透性过渡孔的激活，从而防止雌激素引起的线粒体Ca（2+）螯合增加。雌激素的抗氧化作用可能会增强这些作用，从而阻止有害的“线粒体螺旋”的产生。这些机制中的每一种对由雌激素诱导的总体主动防御状态的贡献程度尚待确定。然而，级联反应的各个方面似乎对雌激素的神经保护作用具有显着影响，即使不是强制性的影响。此外，级联的每个成分对于线粒体功能的雌激素调节都是必需的。在雌激素疗法的临床应用和脑选择性雌激素或NeuroSERMs设计的背景下，考虑了雌激素作用的机制以及预防或治疗阿尔茨海默氏病的雌激素疗法的临床疗效结果。

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